Reflex increases in sympathetic neural discharge during exercise are thought to be mediated, in part, by local metabolites acting on thin-fiber afferent nerve endings in the contracting muscles. While the discharge of these afferents is thought to signal a mismatch between blood flow and muscle metabolism, the specific metabolic events the initiate this reflex are unknown. The overall aim of this proposal is to test the hypothesis that glycolytic flux and pH in active muscle are important in causing the reflex activation of sympathetic outflow produced by muscle contraction in humans. Intraneural recordings of peroneal muscle sympathetic nerve activity (MSNA) and simultaneous 31P nuclear magnetic resonance assessment of intracellular pH and high energy phosphate metabolites in exercising forearm muscles will be performed in conscious humans to determine if 1) reflex increases in MSNA during exercise are specifically linked to glycolytic flux and decreases in muscle cell pH; 2) reflex sympathetic nerve responses to handgrip exercise are altered in patients with specific inborn errors of skeletal muscle metabolism, conditions that cause major alterations in the muscle pH response to contraction; and 3) reflex increases in MSNA are attenuated in normal subjects when the contraction- induced decreases in muscle cell pH are blunted by glycogen depletion of the forearm muscles. Hydrogen ion-selective electrodes will also be used to monitor muscle tissue pH, i.e., in the proximity of the extracellular afferent nerve endings, to determinant of contraction-induced increases in muscle sympathetic outflow during forearm exercise. The distinctive features of these experiments are: the use of several technological advance in neurophysiology (microneurography) and biochemistry (31P NMR, ion- specific tissue electrodes) to pursue basic mechanisms of neural control of the circulation during exercise in conscious humans; and the use of several interventions both in healthy subjects an in patients with specific inborn errors of skeletal muscle metabolism to study metabolic regulation of reflex sympathetic discharge. These experiments should provide new insights into both basic mechanisms of neurocirculatory regulation during exercise in normal individuals as well as in pathophysiologic states associated with muscle hypoperfusion, such as in patients with congestive heart failure and peripheral vascular disease.